Examples of the dithia or vasopressin antagonist art are U.S. Pat. Nos. 4,469,679, 4,481,193, 4,481,194 and 4,491,577.
Carba analogues of oxytocin and vasopressin, which have agonist activity, have been repeatedly reported in the prior art, such as in U.S. Pat. Nos. 3,980,631, 4,285,858, 4,482,486, 4,237,119 as well as in F. Fahrenholz et al., Biochem. Biophys. Res. Com. 122, 974 (1984) and J. Biol. Chem. 258 14861 (1983). Dicarba or 1,6-amino-suberic acid analogs of lysine- and arginine-vasopressin and oxytocin have been reported to have variable agonist activity. These prior art structures have no substituent on the 1,6-suberic acid and are agonists, i.e. they have the same biological activity as do vasopressin (VSP) or oxytocin (OXT).
We have now found that, when the 1-unit and the dithia connection of certain vasopressin structures is replaced by a 6,6-spiroalkylenesuberic acid, the resulting compounds have potent, even enhanced antagonist activity, especially aquaretic activity.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form.
Certain of the peptide art designations used herein are the following: Pas, 6,6-cyclopentamethylene-2-aminosuberic acid; Tas, 6,6-cyclotetramethylene- 2-aminosuberic acid; Pas(Bzl), .omega.-benzyl ester of Pas; Abu, .alpha.-amino-n-butyric acid; Cad, cadaverine; Chg, cyclo hexylglycine; Cha, cyclohexylalanine; Thr, threonine; Pba, .alpha.-aminophenylbutyric acid; Gln, glutamic acid amide or glutamine; Pro, proline, .DELTA.Pro, .alpha..sup.3 -proline; Gly, glycine; Tyr, tyrosine; Tyr(Alk), lower alkyl ether of Tyr; Phe, phenylalanine; Phe(4'-Alk), 4'-alkylphenylalanine; MeAla, N methylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine; Lys, lysine; Arg, arginine; HArg, homoarginine; MeArg, N-methylarginine; MeHArg, N-methylhomoarginine; MeLys, N-methyllysine; Met, methionine; Asn, asparagine; Put(G), 1-amino-4-guanidinobutane (--NH(CH.sub.2).sub.4 NHC(NH.sub.4)NH.sub.2); Glu, glutamic acid; Orn, ornithine; Asp, aspartic acid, MeOrn, N-methylornithine; Tos, tosylate; BHA, benzhydrylamine; DMAP, 4-dimethylaminopyridine; DIEA, diisopropylethylamine; Trp, tryptophan; HF, hydrogen fluoride; 4-MeBzl, 4-methyl benzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbo diimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HBT, hydroxybenzotriazole. In the definitions such as MeArg above, Me denotes a methyl located on the amido nitrogen of the peptide unit concerned. The designation, Pas.sup.1,6 , is used to denote the cyclized peptide as described hereafter.
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the oxygen substituent of a tyrosine unit at position 2 of the peptide of formula I, to the N terminal nitrogen of the tail, or to the 4'-position of a Phe unit at position 2 or of the peptide of formula I. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. Ethyl is preferred. When the term "vasopressin" is used, it means L arginine vasopressin (AVP) unless otherwise modified.